b i o m e d i c a l j o u r n a l 3 9 ( 2 0 1 6 ) 3 5 4 e3 6 0

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Biomedical Journal
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Original Article

Profile of glycated-hemoglobin, antioxidant

vitamin and cytokine levels in pulmonary
tuberculosis patients: A cross sectional study at
Pulmonary Diseases Center Semarang City,
Indonesia

Praba Ginandjar a,*, Lintang Dian Saraswati a, Bagoes Widjanarko b,c

a
Department of Epidemiology and Tropical Diseases, Faculty of Public Health, Diponegoro University, Indonesia
b
Department of Health Promotion, Faculty of Public Health, Diponegoro University, Indonesia
c
Tuberculosis Operational Research Group (TORG), Indonesia

article info abstract

Article history: Background: Uncontrolled blood glucose, which marked by high level of HbA1c, increases
Received 29 June 2015 risk of pulmonary TB because of cellular immunity dysfunction. This study aimed to
Accepted 21 January 2016 analyze profile of glycated hemoglobin, antioxidant vitamins status and cytokines levels in
Available online 9 November 2016 active pulmonary TB patients.
Methods: This was a cross sectional study, conducted at Pulmonary Diseases Center Sem-
Keywords: arang City, Indonesia. Study subject consisted of 62 pulmonary TB patients, diagnosed with
HbA1c positive acid fast bacilli and chest X-ray. ELISA was used to measure IFN-g and IL-12. Status
Pulmonary tuberculosis of antioxidant vitamins was determined by concentration of vitamin A and E using HPLC.
Vitamin A Blood glucose control was determined by HbA1c concentration (HbA1c
7% is considered
Vitamin E as uncontrolled).
Results: A significant difference of age between pulmonary tuberculosis patients with
normal and uncontrolled blood glucose (p 0.000) was showed, while all other charac-
teristics (sex, education, occupation) did not differ with p 0.050, 0.280, 0.380 respectively.
Mean HbA1c was 7.25 2.70%. Prevalence of uncontrolled glucose among pulmonary TB
patients was 29%. Levels of IFN-g and IL-12 did not differ according to HbA1c concentration
(p 0.159 and p 0.965 respectively). Pulmonary tuberculosis patients with uncontrolled
blood glucose has higher vitamin E (p 0.006), while vitamin A did not differ significantly
(p 0.478).
Conclusions: This study supports the importance of performing diabetes screening among
pulmonary TB patients. Further study needs to be done to determine the feasibility of TB-
DM co-management.

* Corresponding author. Department of Epidemiology and Tropical Diseases, Faculty of Public Health, Diponegoro University, Jl. Prof.
Soedarto SH, Kampus UNDIP Tembalang, Semarang 50275, Indonesia. Tel.: 62 81325887942; fax: 62 247460044ext.102.
E-mail address: praba.ginandjar@live.undip.ac.id (P. Ginandjar).
Peer review under responsibility of Chang Gung University.
http://dx.doi.org/10.1016/j.bj.2016.01.011
2319-4170/ 2016 Chang Gung University. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 b i o m e d i c a l j o u r n a l 3 9 ( 2 0 1 6 ) 3 5 4 e3 6 0
At a glance commentary
Scientific background on the subject
Indonesia has a second largest burden of tuberculosis
globally, and had 10 million cases of diabetes in 2015.
Relationship of tuberculosis and diabetes is more
prominent in developing countries, where TB is endemic
and the burden of diabetes mellitus is increasing. Early
detection uncontrolled glucose and antioxidant vitamins
in pulmonary tuberculosis patients may give benefit to
control the diseases.
What this study adds to the field
Almost one third of PTB patients had HbA1c levels >7%.
The group of pulmonary tuberculosis with high HbA1c
levels had similar levels of vitamin A, IFNg, and IL-12. On
the other hand, vitamin E levels was higher in HbA1c > 7.
Management of co-morbidities need to prioritize at risk
group. This study supports the importance of performing
blood glucose screening among pulmonary tuberculosis
patients.
Glycated hemoglobin, commonly known as HbA1c, reflects
an average blood glucose levels over a period of weeks or
months. The International Expert Committee has recom-
mended HbA1c for diabetes diagnosis [1]. Worldwide, the In-
ternational Diabetes Federation (IDF) predicts that the number
of people with diabetes will rise by 55% in the next 20 years [2].
The current pandemic of type 2 diabetes mellitus is acceler-
ating in a world where approximately one third of the popu-
lation is latently infected with Mycobacterium tuberculosis [3].
Diabetes patients have 2e5 times higher risk to develop
tuberculosis compared to non-diabetes [4,5]. Once infected,
diabetes patients need longer treatment and are at risk of drug
resistance [6] and treatment failure [7]. Furthermore, a study
in Indonesia revealed pulmonary tuberculosis patients with
co-existence of diabetes had more clinical signs compared to
non-diabetes [8].
Uncontrolled blood glucose, which marked by high level of
glycated hemoglobin (HbA1c) [9], is one of TB risk factors [10].
Risk of active tuberculosis development in population with
diabetes [4,11,12] may relate to lower antimicrobial peptide
gene expression [13]. The lower antimicrobial peptide gene
expression may also increase the risk of tuberculosis reac-
tivation [13,14] and modifies clinical sign of pulmonary
tuberculosis [15]. Diabetes patients are also prone to pulmo-
nary TB infection due to phagocytosis [16] and cellular im-
munity [17] dysfunctions, the two main immune responses to
M. tuberculosis [18].
Pulmonary tuberculosis and diabetes are often associated
with malnutrition. The link between nutritional status and
tuberculosis has long been appreciated, but remains an
emerging area of study that has focused on investigations of
related biomarkers and nutrient supplementation trials [19].
355
Pulmonary tuberculosis patients frequently suffer from de-
ficiencies in antioxidant micronutrients, such as vitamins A
and E. Both are fundamental vitamins to the integrity of the
immune response, especially the host's immune response
against M. tuberculosis. Furthermore, vitamins play an impor-
tant role in glucose metabolism [20]. Vitamins also related
with active pulmonary tuberculosis. A previous study showed
that the levels of vitamin C and vitamin E were significantly
decreased in M. tuberculosis patients when compared to the
healthy controls [21].
Both diabetes and pulmonary tuberculosis patients are
usually underdiagnosed, or delayed diagnosed [22]. Early
detection of diabetes through blood glucose indicator in pul-
monary tuberculosis patients, along with the underlying fac-
tors might play role in co-management of the diseases in
question. In this study, we analyzed the cytokines (IFN-g and
IL-12), antioxidant vitamin (vitamin A and E), and blood
glucose control (HBA1c) in active pulmonary TB patients.
Methods
Study subject
Subject was pulmonary tuberculosis patients, who sought
treatment at Pulmonary Health Center (called BKPM Balai
Kesehatan Paru Masyarakat) Semarang City, Indonesia [Fig. 1].
Patients were selected by pulmonary tuberculosis symptoms
as follow: persistent cough for more than 3 weeks, produce
sputum, and loss weight. Two same-day sputum specimens
were collected and examined for sputum smear microscopy
by Ziehl Neelsen staining, and detected to have acid fast bacilli
on sputum examination [23]. Patients also underwent chest X-
ray to examine the existence of tuberculosis cavities. HIV
serology test was done to all pulmonary tuberculosis suspects
for exclusion criteria.
Eligible subjects were selected consecutively during June
11eAugust 23, 2014. During the course of study, there were 85
patients diagnosed as pulmonary tuberculosis, 23 of them
either refused to join the study or experienced difficulties
during blood collection. Overall, there were 62 pulmonary
tuberculosis patients became our study subject. All subjects
agreed to join the study by signing written informed consent.
Ethical clearance was obtained from the Commission of Ethics
of Medical and Public Health Research, Faculty of Public
Health, Diponegoro University (number: 298/EC/FKM/2013).
Data collection
Variables in this study were pulmonary tuberculosis occur-
rence, body mass index (BMI), IFN-g, IL-12, vitamin A, vitamin
E, HbA1c levels, characteristics (age, sex, education, occupa-
tion), and history of diseases history of diseases (diabetes,
high blood pressure, hypercholesterolemia). Pulmonary TB
referred to patients with M. tuberculosis infection, which is
characterized by detection of acid fast bacilli in sputum using
Ziehl Neelsen examination and chest X-ray. Body mass index
was derived from ratio of body weight in kilogram to body
height in centimeter. Education was categorized as basic
356 b i o m e d i c a l j o u r n a l 3 9 ( 2 0 1 6 ) 3 5 4 e3 6 0

Suspect pulmonary tuberculosis at

Pulmonary Health Center, determined
by persistent cough > 3 weeks, sputum,
loss weight (n=422)

Fulfill eligibility, determined by positive

fast acid bacilli in Ziehl Neelsen staining Did not fulfill eligibility (n=337)
and cavity from chest x-ray (n=85)

Agreed to participate in the study Refused to participate in the study

(n=62) (n= 23)

HbA1c 7 %
(n=18)

HbA1c < 7 %
(n=44)

Fig. 1 e Flow diagram of study subject participation.

(elementary to junior high school) and high education (senior
high school and college). Occupation was categorized as
employed and unemployed.
IFN-g and IL-12 were examined using Quantikine HS ELISA
kits and read in 450 nm. Vitamin A was measured in the form
of retinol serum concentration indicator, using HPLC exami-
nation and stated in mg/L. Vitamin A below 200 mg/L is
considered as deficiency. Vitamin E was measured in the form
of alpha tocopherol, which preferentially absorbed and accu-
mulated in human. The measurement also used HPLC, which
stated in mg/L, and value <3 mg/L is considered as deficiency.
HbA1c levels was measured as mean of blood glucose con-
centration in form of glycated hemoglobin using HPLC ex-
amination in %. HbA1c indicates blood glucose control within
previous three months, and is considered as diabetes if its
exceeds recommendation borderline of 7%. All laboratory
examination was conducted at R&E Unit, Prodia Laboratory,
Indonesia.
differ significantly from each other [Table 2]. Mean HbA1c
levels of all subjects was 7.25%. Mean of vitamin A from all
subjects (307.29 mg/L) were considered as normal (200e800 mg/
L). Mean concentration of vitamin E of all subjects (14.94 mg/L)
was slightly higher than normal (8e14 mg/L) [Table 3].
Pulmonary tuberculosis patients with high HbA1c levels
had similar vitamin A, IFN-g and IL-12 with those with normal
HbA1c. Statistical analysis also proved the vitamin A, IFN-g
and IL-12 did not differ significantly between both groups
(p 0.159, 0.965 and 0.478 respectively). On the other hand,
pulmonary tuberculosis patients with HbA1c
7% had higher
vitamin E concentration (16.78 3.49 mg/L) compared to the
normal group (14.18 3.17 mg/L). The difference of vitamin E
levels was statistically significant (p 0.006).
Discussion

Data analysis Our study showed most of pulmonary tuberculosis patients

Distribution of data was determined by KolmogoroveSmirnov
test. Independent t-test was used to analyze data the differ-
ence of IFN-g and IL-12, vitamin A and vitamin E concentra-
tion in pulmonary tuberculosis patients with uncontrolled
and normal blood glucose levels. The difference of charac-
teristics was analyzed with chi-square (education, occupa-
tion, history of diseases) and independent t-test (age).
Results
were male, i.e. 67.7% (in all subjects), 77.8% (in normal HbA1c
group) and 63.6% (in high HbA1c group). This result is in
accordance with previous descriptive epidemiology studies in
Indonesia [24] and worldwide [25e27]. Men seem to be more
affected than women, with a male/female ratio of 1.9 0.6 for
the worldwide case notification rate [28]. The global tubercu-
losis epidemic is also characterized by significant differences
in prevalence between men and women. Rates of tuberculosis
are much higher among men than women in large areas of the
world, and it has been extensively documented [29].

Our study showed 18 out of 62 (29.0%) pulmonary tuberculosis

Table 1 e Prevalence of blood glucose control among
patients had uncontrolled blood glucose, which was indicated pulmonary tuberculosis patients.
by HbA1c levels >7% [Table 1]. There was a significant differ-
HbA1c levels n 62 %
ence between age (p 0.000) and diabetes history (p 0.000) of
pulmonary tuberculosis patients with high and normal gly-
7% 18 29.0
<7% 44 71.0
cated hemoglobin levels, while all other variables did not
 b i o m e d i c a l j o u r n a l 3 9 ( 2 0 1 6 ) 3 5 4 e3 6 0 357

Table 2 e Characteristics of pulmonary tuberculosis patients.

Variables All subject (n 62) HbA1c
7% (n 18) HbA1c <7% (n 44) p
Age (years) 40.06 15.46 52.72 9.27 34.89 14.51 0.000a
BMI (kg/m2) 19.19 3.22 20.44 3.84 18.68 2.83 0.050a
Sex: male 67.7% 63.6% 77.8% 0.280b
Education: basic 58.1% 54.5% 66.7% 0.380b
Occupation: unemployed 27.5% 31.8% 16.7% 0.225b
History of diabetes 21.0% 66.7% 2.3% 0.000b
History of high blood pressure 12.9% 11.1% 13.6% 0.788b
History of hypercholesterolemia 6.5% 16.7% 2.3% 0.127b
a
Independent t-test.
b
Chi-square test.

Age of subjects was mostly in productive ages, with most of
them were 17e35 years of old. Descriptive epidemiology
studies have previously found the same pattern [30,31]. Recent
study revealed polymorphism in mannose lectin (MBL) is the
factor affected high case of tuberculosis in productive ages
[32]. When associated with HbA1c levels, our result indicated
mean age of pulmonary tuberculosis patients with HbA1c
7%
(52.72 9.27 years) was higher than those with normal HbA1c
(34.89 14.51 years). A previous study showed that tubercu-
losis patients with diabetes condition tends to found in older
age [33]. We suggest health institutions with tuberculosis
service to pay attention on patients with higher risk of co-
morbidities such as diabetes. Identification of the high risk
groups allows the health institutions to prioritize age groups
that needs to gain more attention in management of co-
morbidities, in this case tuberculosis and diabetes.
Prevalence of pulmonary tuberculosis patients who have
uncontrolled blood glucose with HbA1c
7% was 29.0%. The
prevalence is in accordance with previous report that one
third of the diabetes population is latently infected with M.
tuberculosis [3]. Our study revealed most of subject with HbA1c

7% had history of diabetes (12 out of 18 subjects). This needs
attention since impaired glucose tolerance is a significant risk
factor for developing diabetes [34]. A previous study showed
tuberculosis subjects had more comorbidities than population
control subjects, including diabetes [25]. The relationship be-
tween diabetes and tuberculosis is bi-directional [12]. This
study supports the importance of performing diabetes
screening among pulmonary TB patients. Further study needs
to be done to determine the feasibility and cost-effectiveness
of co-management of TB-DM.
Our study showed a higher concentration of vitamin E in
pulmonary tuberculosis patients with HbA1c
7%. Vitamin E
is the most important lipid phase chain breaking antioxidants,
and is central to the prevention of lipid peroxidation [21].
Tuberculosis patients usually demonstrate high levels of lipid
peroxidase and low concentration of plasma vitamin E [35].
Lipid peroxidation has also been considered as an early
marker for diabetes [36].
Previous studies observed that vitamin E was significantly
depleted in tuberculosis patients when compared with
healthy individuals [21,37]. Administration of micronutrients,
including vitamin E, has been shown to enhance antioxidant
status [35] and accelerate tuberculosis healing [38]. Vitamin E
presumably will also give benefit to tuberculosis patients with
diabetes. An in vivo study revealed supplementation with
vitamin E significantly reduced glycemia and glycated hemo-
globin (HbA1c) values in diabetic rats [39]. A similar result was
also shown from an experiment study in diabetic patients,
which demonstrated that administration of vitamin E
decreased HbA1c levels in patients with inadequate glycemic
control (HbA1c
8%) and low vitamin E levels [40].
Our study found vitamin A did not differ between pulmo-
nary tuberculosis patients with normal and inadequate blood
glucose control. The result was in contrary with a previous
study that showed tuberculosis and diabetes often coincide
with micronutrient deficiency, including vitamin A [20].
Several studies worldwide observed low level of vitamin A in
tuberculosis patients [41e43]. However, the effect of vitamin A
supplementation on tuberculosis patients in Indonesia varies
according to nutritional status of the patients. In patients with
good nutritional status, supplementation of vitamin A resul-
ted in earlier sputum smear conversion [44]. On the contrary,
vitamin A supplementation failed to reduce sputum conver-
sion time in severely malnourished patients [45].
Various studies have shown the benefits of both vitamin E
and vitamin A in tuberculosis patients, or in diabetes patients
separately. Yet to the best of our knowledge, there has been no

Table 3 e Status of HbA1c, cytokines and vitamins of pulmonary tuberculosis patients.

Variables Mean SD (n 62) Minemax pa
HbA1c (%) 7.25 2.70 4.4e14.4
HbA1c
7% HbA1c <7%
IFN-g 19.14 13.31 22.76 12.02 17.63 13.66 0.82e48.5 0.159
IL-12 2.58 1.63 2.57 1.57 2.58 1.67 0.5e8.42 0.965
Vitamin A (mg/L) 307.29 149.55 328.78 184.09 298.50 134.37 93e883 0.478
Vitamin E (mg/L) 14.94 3.45 16.78 3,49 14.18 3.17 8e25 0.006
a
Independent t-test.
358 b i o m e d i c a l j o u r n a l 3 9 ( 2 0 1 6 ) 3 5 4 e3 6 0
research to study the effect of vitamin E or vitamin A in
tuberculosis with inadequate glycemic control (high HbA1c).
Therefore, comparison with existing literature could not be
made. We found Wang et al. (2013) conducted a randomized
controlled trial to determine the effect of vitamin A in the
form of retinol on treatment of active pulmonary tuberculosis
[20], but the result has not been published.
Our study also did not found difference of IL-12 and IFN-g
in pulmonary tuberculosis patients with normal or HbA1c

7%. This is possibly due to both tuberculosis and uncon-
trolled glucose contribute in decreasing IL-12 and IFN-g, thus
resulting in similar cytokines profile. A longitudinal study by
Tsukaguchi showed tuberculosis patients whose blood
glucose was under control in six months will undergo an
improvement in IFN-g production. On the contrary, IFN-g
levels in tuberculosis patient with high or uncontrolled blood
glucose remained low. This means production of IFN-g is
more related to blood glucose status than to history of dia-
betes [46].
T cell-mediated immune responses are important in the
host control of M. tuberculosis infection. This is evident from the
increased risk of tuberculosis in individuals with deficiencies
in their IFNg and IL-12; which promotes TH1 cell differentiation
signaling pathways [47]. When associated with blood glucose,
the results from previous studies were contradictory. Gomez
(2013) showed monocytes from diabetic patients express the
decrease of IL-12 and IFN-g secretion in vitro, but the relation
was affected by interaction with bacteria [48]. Chu (2015)
revealed glucose increases IL-12 production in stimulated
PBMCs of diabetes patients through increased IL-12 gene
expression [49]. An experiment in streptozotocin-induced
mouse showed that M. tuberculosis infection causes IL-12 and
IFN-g to decrease [18]. A metabolomic study to determine
whether there is a direct functional connection between serum
abundance of metabolites and of immune mediators found
significantly elevated serum concentrations of IFN-g and sol-
uble alpha chain of the IL-2 receptor alpha in TB active patients
as compared to the two healthy groups [50].
There were several limitation of this study. The diagnosis of
pulmonary tuberculosis did not include culture. This was
related to tuberculosis program in Indonesia that only uses fast
acid bacilli detection and X-ray. In addition, history of diabetes
was only determined from interview with subjects and medical
record if any, not by fasting and postprandial glucose serum
levels. The level of nonresponse is also a concern. Proportion of
eligible subjects who refused to participate in this study was
27% (23 out of 85 eligible patients). Therefore, generalization
must be taken with caution due to sample size. Besides, this
study used cross sectional design, which cause difficulty to
establish relation between outcome and exposure of long
duration like pulmonary tuberculosis and high blood glucose.
A longitudinal design should be considered to investigate the
role of underlying factors of pulmonary tuberculosis in
conjunction with HbA1c levels.
Conclusions
Nearly one third of pulmonary tuberculosis patients in this
study (29.0%) contracted with uncontrolled blood glucose,
which was indicated by HbA1c levels >7%. Overall, mean
HbA1c was 7.25%. Pulmonary tuberculosis patients with
HbA1c
7% had higher age, BMI, IFN-g, vitamin A and vitamin
E levels. However, only vitamin E that significantly difference
in pulmonary tuberculosis patients according to HbA1c levels.
Identification of high risk groups allows the health in-
stitutions to prioritize age groups that needs to gain more
attention in management of co-morbidities, in this case
tuberculosis and diabetes. This study supports the importance
of performing diabetes screening among pulmonary TB pa-
tients. Further study needs to be done to determine the
feasibility and cost-effectiveness of co-management of TB-
DM.
Conflicts of interest
We declare that we have no conflict of interest.
Acknowledgement
This study was supported by the Directorate General of the
Higher Education Ministry of Education and Culture and the
Research Institute of Diponegoro University (grant number
180-40/UN7.3.9/PG/2014). The sponsor had no role in the study
design, collection, analysis or interpretation of data.
The authors thank to Pulmonary Health Center of Semar-
ang, Central Java, Indonesia for facilitate the study and to Mr.
Muh. Fauzi for assistance with participant enrollment.
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